Visna was originally recognized in Iceland, as a naturally occurring fatal central nervous system disease of sheep, and was described by Sigurdsson as one of the prototypes of slow infection. The causal agent is now classified as an oncornavirus, based on its physical, biochemical, and biological properties. Following intracerebral inoculation of susceptible Icelandic sheep, a persistent infection develops followed by a late appearance of neutralizing antibodies. Clinical disease appears in 6 months to years after inoculation, and is characterized by a severe lymphocytic infiltration of leptomeninges and choroid plexus, with marked perivascular cuffing and eventual destruction of white matter. The proposed study postulates that the disease is immunopathological in nature and will attempt to elucidate: (1) the cellular sites of virus replication; (2) the role of the immune response (antibody and cell-mediated) in disease production; and (3) the mechanisms of virus persistence. Approaches will include (a) a sequential study of infection in Icelandic sheep; (b) the effect of immunosuppression, using anti-lymphoid serum or cyclophosphamide; (c) the effect of active immunization before and after inoculation; (d) the correlation of various measures of antibody and cell-mediated immunity with disease progression; (e) a search for evidence of an auto-immune response against myelin antigens; and (f) the influence of age at inoculation upon the course of infection.